Zhang Yan-qiong, Wang Song-song, Zhu Wei-liang, Ma Yan, Zhang Fang-bo, Liang Ri-xin, Xu Hai-Yu, Yang Hong-jun
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
1] Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China [2] School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China.
Acta Pharmacol Sin. 2015 Jun;36(6):724-33. doi: 10.1038/aps.2014.124. Epub 2015 May 4.
Huanglian-jie-du decoction (HLJDD) is an important multiherb remedy in TCM, which is recently demonstrated to be effective to treat ischemic stroke. Here, we aimed to investigate the pharmacological mechanisms of HLJDD in the treatment of ischemic stroke using systems biology approaches.
Putative targets of HLJDD were predicted using MetaDrug. An interaction network of putative HLJDD targets and known therapeutic targets for the treatment of ischemic stroke was then constructed, and candidate HLJDD targets were identified by calculating topological features, including 'Degree', 'Node-betweenness', 'Closeness', and 'K-coreness'. The binding efficiencies of the candidate HLJDD targets with the corresponding compositive compounds were further validated by a molecular docking simulation.
A total of 809 putative targets were obtained for 168 compositive compounds in HLJDD. Additionally, 39 putative targets were common to all four herbs of HLJDD. Next, 49 major nodes were identified as candidate HLJDD targets due to their network topological importance. The enrichment analysis based on the Gene Ontology (GO) annotation system and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway demonstrated that candidate HLJDD targets were more frequently involved in G-protein-coupled receptor signaling pathways, neuroactive ligand-receptor interactions and gap junctions, which all played important roles in the progression of ischemic stroke. Finally, the molecular docking simulation showed that 170 pairs of chemical components and candidate HLJDD targets had strong binding efficiencies.
This study has developed for the first time a comprehensive systems approach integrating drug target prediction, network analysis and molecular docking simulation to reveal the relationships between the herbs contained in HLJDD and their putative targets and ischemic stroke-related pathways.
黄连解毒汤是中医一种重要的多味草药方剂，最近被证明对治疗缺血性中风有效。在此，我们旨在运用系统生物学方法研究黄连解毒汤治疗缺血性中风的药理机制。
使用MetaDrug预测黄连解毒汤的潜在靶点。然后构建黄连解毒汤潜在靶点与已知缺血性中风治疗靶点的相互作用网络，并通过计算拓扑特征（包括“度”“节点中介中心性”“紧密性”和“K核数”）来识别黄连解毒汤的候选靶点。通过分子对接模拟进一步验证候选黄连解毒汤靶点与相应复合化合物的结合效率。
黄连解毒汤中的168种复合化合物共获得809个潜在靶点。此外，黄连解毒汤的所有四味草药共有39个潜在靶点。接下来，由于其网络拓扑重要性，49个主要节点被确定为黄连解毒汤的候选靶点。基于基因本体（GO）注释系统和京都基因与基因组百科全书（KEGG）通路的富集分析表明，候选黄连解毒汤靶点更频繁地参与G蛋白偶联受体信号通路、神经活性配体-受体相互作用和缝隙连接，这些在缺血性中风的进展中都起着重要作用。最后，分子对接模拟表明170对化学成分与候选黄连解毒汤靶点具有较强的结合效率。
本研究首次开发了一种综合系统方法，整合药物靶点预测、网络分析和分子对接模拟，以揭示黄连解毒汤所含草药与其潜在靶点以及缺血性中风相关通路之间 的关系。
